Isoform D of vascular endothelial growth factor in systemic capillary leak syndrome : a case report

Background: Systemic capillary leak syndrome is a rare condition characterized by episodic attacks of hypovolemia due to systemic capillary hyperpermeability, which results in profound hypotension and edema. Although the implication of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 has been suggested, the pathogenesis of systemic capillary leak syndrome remains unclear. In this report, we describe a case of systemic capillary leak syndrome in which serum isoform D of vascular endothelial growth factor was elevated. To the best of our knowledge, this is the first reported case of systemic capillary leak syndrome in which isoform D of vascular endothelial growth factor is suggested as the plausible biomarker. Case presentation: A 41-year-old Japanese man was transferred to our emergency department. He was hypotensive, tachycardic, and edematous over the trunk and all four limbs. He received aggressive intravenous fluid therapy and underwent fasciotomy of the right forearm to prevent muscle necrosis. A diagnosis of systemic capillary leak syndrome was suspected. The presence of serum monoclonal immunoglobulin G and κ light chain supported this diagnosis. Prevention of hypotensive crises was unsuccessfully attempted with theophylline, intravenous immunoglobulin, high-dose dexamethasone, bortezomib, melphalan, and prednisolone; however, the patient’s attacks dramatically disappeared after the introduction of thalidomide. The serum of the patient was stored soon after the onset of hypotensive crisis and analyzed to profile possible mediators responsible for the capillary leak. The concentration of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 were all within normal ranges. Meanwhile, we found that isoform D of vascular endothelial growth factor was elevated, which was normalized after the introduction of thalidomide. Conclusions: In our patient, isoform D of vascular endothelial growth factor (instead of vascular endothelial growth factor) may have been a causative factor of hypotensive crises, since isoform D contributes to vascular endothelial growth factor receptor-2 signaling, which is the major mediator of the permeability-enhancing effects of vascular endothelial growth factor. We suggest the measurement of isoform D of vascular endothelial growth factor in patients with systemic capillary leak syndrome in whose serum vascular endothelial growth factor is not elevated

Phase I/IIa Study of Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease

Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT

Denosumab prevents bone loss in newly diagnosed malignant lymphoma patients undergoing corticosteroid-containing chemotherapy: a prospective, non-randomized study

Background: Malignant lymphoma patients have a high risk of bone mineral density (BMD) loss caused by corticosteroid-containing chemotherapy. Bisphosphonates have been used to prevent bone loss: however, little is known about effects of denosumab, a fully humanized monoclonal antibody inhibiting osteoclast-mediated bone resorption. Methods: This clinical trial was conducted in newly diagnosed lymphoma patients undergoing corticosteroid-containing chemotherapy. BMD was evaluated at baseline, and patients with a lumbar spine T-score of ? -1 were subcutaneously administered once with 60 mg of denosumab (“Denosumab” group). Patients with a T-score > -1 were allocated to the “No treatment” group. BMD was reevaluated at 24 weeks after enrollment. Bone turnover markers (BTMs) were collected at 0, 2, and 24 weeks.Results: Forty-three patients were enrolled (19 in the “Denosumab” group and 24 in the “No treatment” group). Patients in the “No treatment” group had decreased T-scores for the lumbar spine or femoral neck (P < 0.0001 or P = 0.0029, respectively) at 24 weeks after enrollment, whereas both T-scores were stable in the “Denosumab” group. Of the 18 patients in the “Denosumab” group, 12 had a T-score change from baseline (ΔT-score) of ? 0, whereas the remaining six patients had a ΔT-score < 0. These six patients had severely low T-scores at enrollment. Osteoclastic BTMs were strongly suppressed during the 24 weeks in the “Denosumab” group. The probability of major osteoporotic fracture or hip fracture in the “No treatment” group increased during the 24 weeks (P = 0.0195 or P = 0.0289, respectively), whereas pretreatment with denosumab prevented increased risks of both types of fractures. Conclusions: Our data suggests that BMD screening at diagnosis of lymphoma should be considered so that the bone health of lymphoma survivors can be improved with denosumab

Denosumab prevents bone loss in newly diagnosed malignant lymphoma patients undergoing corticosteroid-containing chemotherapy: a prospective, non-randomized study

Background: Malignant lymphoma patients have a high risk of bone mineral density (BMD) loss caused by corticosteroid-containing chemotherapy. Bisphosphonates have been used to prevent bone loss: however, little is known about effects of denosumab, a fully humanized monoclonal antibody inhibiting osteoclast-mediated bone resorption. Methods: This clinical trial was conducted in newly diagnosed lymphoma patients undergoing corticosteroid-containing chemotherapy. BMD was evaluated at baseline, and patients with a lumbar spine T-score of ? -1 were subcutaneously administered once with 60 mg of denosumab (“Denosumab” group). Patients with a T-score > -1 were allocated to the “No treatment” group. BMD was reevaluated at 24 weeks after enrollment. Bone turnover markers (BTMs) were collected at 0, 2, and 24 weeks.Results: Forty-three patients were enrolled (19 in the “Denosumab” group and 24 in the “No treatment” group). Patients in the “No treatment” group had decreased T-scores for the lumbar spine or femoral neck (P < 0.0001 or P = 0.0029, respectively) at 24 weeks after enrollment, whereas both T-scores were stable in the “Denosumab” group. Of the 18 patients in the “Denosumab” group, 12 had a T-score change from baseline (ΔT-score) of ? 0, whereas the remaining six patients had a ΔT-score < 0. These six patients had severely low T-scores at enrollment. Osteoclastic BTMs were strongly suppressed during the 24 weeks in the “Denosumab” group. The probability of major osteoporotic fracture or hip fracture in the “No treatment” group increased during the 24 weeks (P = 0.0195 or P = 0.0289, respectively), whereas pretreatment with denosumab prevented increased risks of both types of fractures. Conclusions: Our data suggests that BMD screening at diagnosis of lymphoma should be considered so that the bone health of lymphoma survivors can be improved with denosumab

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling

Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment

High Level of Serum Soluble Interleukin-2 Receptor at Transplantation Predicts Poor Outcome of Allogeneic Stem Cell Transplantation for Adult T Cell Leukemia

The prognosis for adult T cell leukemia/lymphoma (ATL) is very poor, and only allogeneic hematopoietic stem cell transplantation (allo-SCT) has been considered to be a curative treatment for ATL. In this study, we retrospectively analyzed data for patients who had received allo-SCT for ATL in Hokkaido, the northernmost island of Japan, to determine prognostic factors. Fifty-six patients with a median age of 57 years received allo-SCT. Twenty-eight (50.0%) patients had acute type and 22 (46.4%) had lymphoma type. Twenty-three (41.1%) patients received allo-SCT in complete remission (CR), whereas the others were in non-CR. Seventeen (30.4%) patients received myeloablative conditioning and the others received reduced-intensity conditioning. With a median follow-up period of 48 months (range, 17 to 134 months), 1-year overall survival (OS) and 5-year OS rates were 55.4% and 46.1%, respectively. The survival curve reached a plateau at 22 months after stem cell transplantation (SCT). Male sex, high level of serum soluble interleukin-2 receptor (sIL-2R) at SCT, and non-CR at SCT were determined to be significant risk factors for OS. A high level of sIL-2R at SCT was a risk factor for poor OS in patients with non-CR at SCT by univariate analysis (P = .02), and it remained significant after adjustment by sex (hazard ratio, 2.73 [95% confidence interval, 1.07 to 7.90]). A high level of sIL-2R at SCT was also determined to be a risk factor for disease progression (P = .02). This region-wide study showed encouraging results for survival after allo-SCT for ATL and demonstrated for the first time that a high level of sIL-2R at SCT predicts worse SCT outcome. (C) 2014 American Society for Blood and Marrow Transplantation